Stroke is the third leading cause of death and the leading cause of adult disability in developed countries (Simons et al., Stroke 29:1341-6, 1998; Adams et al., Ischemic Cerebrovascular Disease. New York: Oxford, 2001). Strokes are caused by an interruption of blood flow to the brain, by either an intravascular occlusion (such as an arterial thrombus) or a hemorrhage. The American Heart Association estimates that there are approximately three million stroke survivors in the United States, most of whom are disabled. Despite the prevalence and burden of this disease, stroke precipitants and pathophysiological mechanisms in individual patients are often unknown. It is also difficult to accurately predict whether a stroke will lead to only minor neurological sequelae or more serious medical consequences.
Gene expression profiling involves the study of mRNA levels in a tissue sample to determine the expression levels of genes that are expressed or transcribed from genomic DNA. Animal experiments in focally ischemic brain tissue have indicated that there are alterations in gene expression following a stroke (Stenzel-Poore et al., Lancet 362:1028-37, 2003; Lu et al., J. Cereb. Blood Flow. Metab. 23:786-810, 2003; Tang et al., Eur J Neurosci 15:1937-52, 2002; Tang et al., Ann. Neurol. 50:699-707, 2001; and Tang et al., J Cereb Blood Flow Metab 23:310-9, 2003). However, gene expression profiling has not yet been applied to clinical human stroke, primarily because brain tissue samples are inaccessible and rarely justified. Therefore, an assay that can allow one to determine the genetic expression profile of ischemic stroke without the need for brain tissue samples is needed.
Currently, there is no specific blood marker of acute stroke. Following a stroke, released brain antigens can be detected in the blood. Such antigens include S100B, neuron specific enolase (NSE), and glial fibrillary acid protein (GFAP), although S100B and GFAP are of low sensitivity for early stroke diagnosis, and NSE and myelin basic protein (MBP) MBP are non-specific (Lamers et al., Brain. Res. Bull. 61:2614, 2003). Four soluble factors that have demonstrated moderate sensitivity and specificity for the diagnosis of stroke include two markers of inflammation (matrix metalloproteinase-9 and vascular cell adhesion molecule), one marker of glial activation (S100beta) and one thrombosis marker (von Willebrand factor) (Lynch et al., Stroke 35:57-63, 2004). However, a panel of markers which allow one to diagnose and prognose ischemic stroke with high diagnostic sensitivity and specificity is still needed.